The synergistic impact of nonalcoholic fatty liver disease and metabolic syndrome on subclinical atherosclerosis.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a well-known contributor for the development of cardiovascular disease (CVD). We examined the influence of NAFLD and metabolic syndrome (MetS) on markers of subclinical atherosclerosis, including carotid intima-media thickness (CIMT), brachial-ankle pulse wave velocity (baPWV) and ankle-brachial pressure index (ABI), after adjusting for cardiometabolic risk factors. DESIGN: A cross-sectional study. PATIENTS AND MEASUREMENTS: The association between NAFLD, MetS and markers of subclinical atherosclerosis was assessed in 955 participants without CVD using multiple logistic regression analysis after adjusting for multiple cardiometabolic risk variables. RESULTS: After adjusting for age and sex, CIMT and baPWV were found to be significantly correlated with multiple cardiometabolic risk variables, whereas ABI was only associated with obesity parameters. The prevalence of NAFLD differed significantly according to the presence of subclinical atherosclerosis as defined by both CIMT and baPWV (P = 0·004 and P = 0·007, respectively). After adjusting for potential confounding factors, NAFLD or MetS was not associated with subclinical atherosclerosis as defined by CIMT and baPWV. However, individuals with both NAFLD and MetS had a significantly higher risk of subclinical atherosclerosis as defined by CIMT (OR = 2·06, 95% CI = 1·13-3·74) or baPWV (OR = 2·64, 95% CI = 1·46-4·76) compared to normal subjects, even after adjusting for potential confounders. CONCLUSIONS: The results show that NAFLD and MetS have a synergistic impact on the subclinical atherosclerosis, which suggests that individuals with both NAFLD and MetS should be strongly advised to engage in CVD prevention strategies.

BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARδ-dependent pathway in mice.

AIMS/HYPOTHESIS: We explored the effects of ß-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor δ (PPARδ). METHODS: Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knockdown and specific inhibitors. RESULTS: BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt-mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFD-induced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory κBα (IκBα) phosphorylation, nuclear factor κB (NFκB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARδ in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Pparδ (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Pparδ siRNA. CONCLUSIONS/INTERPRETATION: These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPARδ pathway in skeletal muscle.

Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study.

UNLABELLED: Previous studies have shown that nonalcoholic fatty liver disease (NAFLD) and sarcopenia may share pathophysiological mechanisms, such as insulin resistance, inflammation, vitamin D deficiency, and decreased physical activity. However, their direct relationship has not been investigated. The association between NAFLD and sarcopenia was examined in 452 apparently healthy adults enrolled in the Korean Sarcopenic Obesity Study (KSOS), an ongoing prospective observational cohort study. The liver attenuation index (LAI), which was measured using abdominal computed tomography (CT), was used as a parameter for the diagnosis of NAFLD. Sarcopenia was defined using a skeletal muscle mass index (SMI) [SMI (%) = total skeletal muscle mass (kg) / weight (kg) × 100] that was measured by dual energy X-ray absorptiometry (DXA). After adjusting for age and sex, both SMI and LAI were negatively correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) (P < 0.001) and high sensitivity C-reactive protein (hsCRP) (P < 0.001) as well as brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness. Furthermore, SMI and LAI had positive relationships with high-density lipoprotein (HDL)-cholesterol, but both had a negative relationship with triglyceride, alanine aminotransferase (ALT), and total body fat. In a multiple logistic regression analysis, the odds ratio for NAFLD risk was 5.16 (95% confidence interval [CI] = 1.63-16.33) in the lowest quartile of SMI compared to the highest after adjusting for potential confounding factors. CONCLUSION: Individuals with lower muscle mass exhibited increased risk of NAFLD. This result may provide a novel insight into the mechanism linking between sarcopenia and NAFLD. (Clinical trial no. NCT01594710.)

The effects of caloric restriction on fetuin-A and cardiovascular risk factors in rats and humans: a randomized controlled trial.

OBJECTIVES: The liver-secreted protein fetuin-A is associated with insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis. We examined the effect of caloric restriction (CR) on fetuin-A levels and concomitant changes in hepatic steatosis and cardiovascular risk factors in rats and humans. DESIGN AND SUBJECTS: We performed a randomized, controlled clinical trial to examine circulating fetuin-A levels and cardiovascular risk parameters including visceral fat area (VFA), atherogenic lipid profile, inflammatory markers, adipokines levels and brachial artery endothelial function in 76 overweight women with type 2 diabetes before and after 12 weeks of CR. In addition, the effects of CR on hepatic steatosis and fetuin-A mRNA expression were evaluated in Otuska Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and type 2 diabetes. RESULTS: Circulating fetuin-A levels were significantly decreased after 12 weeks of CR and were accompanied by improvements in VFA, blood pressure, glucose, lipid profiles and liver function. The CR group also showed a significant decrease in apolipoprotein B, leptin and insulin resistance compared to those in the control group, although endothelial function was not different. Multiple regression analysis showed that the changes in fetuin-A levels were independently associated with CR and changes in hsCRP and adiponectin (R² = 0·156). Moreover, CR significantly reduced hepatic steatosis and fetuin-A expression, as well as weight, glucose, total cholesterol and triglyceride levels, in OLETF rats. CONCLUSION: Caloric restriction significantly reduced the hepatic expression of fetuin-A and its circulating levels and improved several cardiovascular risk factors in obese rats and humans with type 2 diabetes.

Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women.

OBJECTIVE: We examined the relationship between brachial-ankle pulse wave velocity (baPWV) reflecting arterial stiffness and the levels of novel hepatokines fibroblast growth factor 21 (FGF21) and fetuin-A. In addition, we evaluated the effect of a 3-month combined aerobic and resistance exercise programme on FGF21 and fetuin-A levels as well as arterial stiffness in obese women. METHODS: Forty nondiabetic, obese women (body mass index = 27·6 ± 2·4 kg/m(2) ) were included in the study and were compared before and after a 3-month exercise programme, which was composed of 45 min of aerobic exercise at an intensity of 60-75% of the age-predicted maximum heart rate (300 kcal/session) and 20 min of resistance training (100 kcal/session) five times a week. All exercise sessions were supervised by a professional exercise physiologist. RESULTS: At baseline, baPWV levels were correlated with age, body mass index (BMI), systolic blood pressure (SBP), high density lipoprotein cholesterol, fasting glucose and serum FGF21 levels. In a multiple stepwise regression analysis using baPWV as a dependent variable, baPWV levels were associated with age, BMI, SBP, FGF21 and fetuin-A levels (R(2) = 0·744). After the exercise programme, BMI, waist circumference, SBP, diastolic blood pressure and triglyceride levels were significantly decreased. Moreover, baPWV values were significantly improved (P < 0·001) along with modest decrease in FGF21 levels (P = 0·043). However, fetuin-A levels were not changed significantly (P = 0·202). CONCLUSIONS: A 3-month combined exercise programme decreases the FGF21 levels as well as arterial stiffness in obese Korean women.

Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes.

BACKGROUND: Adipokines contribute directly to the atherosclerotic process, connecting metabolic disorders such as obesity and diabetes to cardiovascular disease. Omentin-1 is a recently discovered novel adipokine, so data about the relationship of this adipokine to vascular health in type 2 diabetes is limited. METHODS: We enrolled 60 people with type 2 diabetes, with or without carotid plaque, and 30 participants with normal glucose tolerance. We measured serum omentin-1, high-sensitivity C-reactive protein (hsCRP) levels, and the homeostasis model assessment of insulin resistance (HOMA-IR), as well as other cardiovascular risk factors. Vascular health was assessed by brachial ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT). RESULTS: Serum omentin-1 levels were significantly decreased in type 2 diabetes patients compared to normal glucose controls and was further reduced in type 2 diabetes patients with carotid plaque compared to those without carotid plaque. Multiple stepwise regression analysis showed that age, systolic blood pressure, history of use of statins, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors, and serum omentin-1 level were independent factors determining baPWV in people with type 2 diabetes (r2 = 0.637). Furthermore, in multivariate logistic regression analysis, circulating omentin-1 level was an independent decisive factor for the presence of carotid plaque in type 2 diabetes patients, even after adjusting for age, gender, body mass index, systolic blood pressure, fasting blood glucose, low density lipoprotein cholesterol, and history of smoking and medication (odds ratio, 0.621; 95% confidence interval, 0.420-0.919; P = 0.017). CONCLUSIONS: Circulating omentin-1 level was independently correlated with arterial stiffness and carotid plaque in type 2 diabetes, even after adjusting for other cardiovascular risk factors and detailed medication history.

Association between vascular inflammation and non-alcoholic fatty liver disease: Analysis by 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND: Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease as well as metabolic syndrome. FDG-PET is a novel imaging technique that detects vascular inflammation, which may reflect rupture-prone vulnerable atherosclerotic plaques. METHODS: Vascular inflammation was measured as the maximum target-to-background ratio (maxTBR), along with various cardiometabolic risk factors in 51 subjects with NAFLD, and compared with 100 age- and gender-matched subjects without NAFLD. The liver attenuation index (LAI), which was measured using computed tomography, was used as a parameter for the diagnosis of NAFLD. RESULTS: After adjusting for age and sex, both maxTBR and LAI values were associated with several cardiometabolic risk parameters. Furthermore, there was a significant inter-relationship between LAI and maxTBR values (r=-0.227, P=0.005). Individuals with NAFLD had higher maxTBR values than those without NAFLD (P=0.026), although their carotid intima-media thickness (CIMT) values did not differ. The proportion of subjects with NAFLD showed a step-wise increment following the tertiles of maxTBR values (P for trend=0.015). In multiple logistic regression analysis, maxTBR tertiles were independently associated with NAFLD after adjusting for age, gender, systolic blood pressure, triglycerides, HDL-cholesterol, glucose, BUN, creatinine and homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.030). However, their relationship was attenuated after further adjustment for waist circumference or high sensitive C-reactive protein. CONCLUSION: Patients with NAFLD have an increased risk for vascular inflammation as measured via FDG-PET/CT even without difference in CIMT. (Clinical trials No. NCT01958411, http://www.clinicaltrials.gov/).

Association of pooled cohort risk scores with vascular inflammation and coronary artery calcification in Korean adults.

OBJECTIVES: A new pooled cohort risk equation to estimate atherosclerotic cardiovascular disease (CVD) risk was recently published, but the equation is based primarily on data from Caucasian populations. The relationship of this new risk scoring system with vascular inflammation and calcification has yet to be examined. METHODS: A total of 74 participants were retrospectively selected based on inclusion and exclusion criteria. All participants underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and multi-detector computed tomography (MDCT) examination in the Korea University Guro Hospital between June 2009 and May 2013. Vascular inflammation of the carotid artery was measured as target-to-background ratio (TBR) using (18)F-FDG-PET/CT and coronary artery calcification was quantified as Agatston score by MDCT. RESULTS: Agatston scores were not significantly associated with any metabolic risk factors, but maximum TBR values exhibited a significant positive correlation with body mass index (r=0.31, P=0.01), waist circumference (r=0.42, P<0.01), waist-to-hip ratio (r=0.49, P<0.01), and systolic (r=0.35, P<0.01) and diastolic blood pressure (r=0.39, P<0.01). Furthermore, maximum TBR values were significantly correlated with serum high-sensitivity C-reactive protein (hsCRP) levels (r=0.26, P=0.03), whereas Agatston scores had no correlation. When pooled cohort risk equation scores were divided into incremental tertiles, age, waist circumference, waist-to-hip ratio and systolic blood pressure showed significant incremental trends. In particular, pooled cohort risk scores exhibited a significant positive correlation with maximum TBR values (r=0.35, P<0.01), but not with Agatston scores (r=0.11, P=0.34). CONCLUSIONS: The pooled cohort risk equation exhibited significant positive correlations with vascular inflammation but not with calcification in Asian subjects without CVD, suggesting that this novel risk equation may detect early inflammatory changes preceding the structural modification of vessel walls.

C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress.

C1q/TNF-Related Protein (CTRP) 9, the closest paralog of adiponectin, has been reported to protect against diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. We explored the protective effect of CTRP9 against hepatic steatosis and apoptosis, and identified the mechanisms through autophagy and endoplasmic reticulum (ER) stress using in vitro and in vivo experiments. Treating HepG2 cells with human recombinant CTRP9 significantly ameliorated palmitate- or tunicamycin-induced dysregulation of lipid metabolism, caspase 3 activity and chromatin condensation, which lead to reduction of hepatic triglyceride (TG) accumulation. CTRP9 treatment induced autophagy markers including LC3 conversion, P62 degradation, Beclin1 and ATG7 through AMPK phosphorylation in human primary hepatocytes. Furthermore, CTRP9 decreased palmitate- or tunicamycin-induced ER stress markers, such as eIF2α, CHOP and IRE-1, in HepG2 cells. Compound C, an AMPK inhibitor, and 3 methyladenine (3 MA), an autophagy inhibitor, canceled the effects of CTRP9 on ER stress, apoptosis and hepatic steatosis. In the livers of HFD-fed mice, adenovirus-mediated CTRP9 overexpression significantly induced AMPK phosphorylation and autophagy, whereas suppressed ER stress markers. In addition, both SREBP1-mediated lipogenic gene expression and apoptosis were significantly attenuated, which result in improvement in hepatic steatosis by overexpression of CTRP9. These results demonstrate that CTRP9 alleviates hepatic steatosis through relief of ER stress via the AMPK-mediated induction of autophagy.

Waist-to-hip ratio is better at predicting subclinical atherosclerosis than body mass index and waist circumference in postmenopausal women.

OBJECTIVE: Body fat distribution becomes more central after menopause. Although some studies have identified the superiority of various anthropometric indices to assess general health outcomes, very limited studies have compared the efficacy of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) to predict subclinical atherosclerosis according to menopausal status. METHODS: In total, 442 participants (209 premenopausal women and 233 postmenopausal women) were prospectively enrolled from the Health Promotion Center of Korea University Guro Hospital. We examined subclinical atherosclerosis using carotid intima-media thickness (CIMT) and brachial-ankle pulse wave velocity (baPWV). RESULTS: In premenopausal women, all anthropometric parameters such as BMI, WC and WHR were positively correlated with baPWV and CIMT values, whereas in postmenopausal women, only WHR was positively correlated with baPWV values (0.27, P<0.01), and WC and WHR were positively correlated with CIMT (0.15, P<0.05 and 0.21, P<0.01, respectively). By receiver operating characteristic (ROC) curve analyses, WHR was superior to the other anthropometric indices to predict carotid atherosclerosis in postmenopausal women. Furthermore, the normal weight (BMI<23kg/m(2)) with higher WHR group had a significantly thicker CIMT when compared to the normal weight with lower WHR group (0.76mm vs. 0.68mm, P<0.01) and even the overweight subjects with BMI≥23kg/m(2) (0.76mm vs. 0.70mm, P<0.01) in postmenopausal women. CONCLUSIONS: The present study shows that WHR has the best potential for predicting subclinical atherosclerosis compared to BMI and WC in postmenopausal women. CLINICAL TRIALS NUMBER: NCT01594710.

LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells.

OBJECTIVE: Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered novel hepatokine, leading to skeletal muscle insulin resistance by activating c-Jun N-terminal kinase (JNK). However, its role in atherosclerotic inflammatory reactions has not been examined. Therefore, we investigated the function of LECT2 on the expression of vascular adhesion molecules and inflammatory cytokines in human endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were treated with various doses of LECT2 and the functions and signaling pathways were analyzed through Western blot and quantitative real-time PCR (qPCR). RESULTS: The level of phosphorylated c-Jun N-terminal kinases (JNK) was significantly increased by LECT2 treatment in HUVECs and THP-1 cells, an effect that was not seen in cells treated with CD209 siRNA, a known LECT2 receptor. LECT2 treatment efficiently increased the expression of intercellular adhesion molecule-1 (ICAM-1) and pro-inflammatory cytokines tumor necrosis factor α (TNFα), monocyte chemo-attractant protein-1 (MCP-1), and interleukin-1ß (IL-1ß) in HUVECs and THP-1 cells. However, all these reactions were significantly reduced in response to treatment with JNK inhibitor. Furthermore, LECT2 treatment significantly exacerbated the adhesion of monocytic cells to human endothelial cells, which was also efficiently attenuated by JNK inhibitor. CONCLUSIONS: LECT2 significantly induced adhesion molecules and pro-inflammatory cytokines in HUVECs via CD209-mediated JNK phosphorylation, suggesting that liver-derived novel hepatokine, LECT2, might directly mediate in the atherosclerotic inflammatory reactions in human endothelial cells.

Vascular inflammation in metabolically abnormal but normal-weight and metabolically healthy obese individuals analyzed with ¹8F-fluorodeoxyglucose positron emission tomography.

Recent studies have suggested that body size phenotype may contribute to atherosclerosis and cardiovascular disease. (18)F-fluorodeoxyglucose (FDG) positron emission tomography is a useful imaging technique for detecting vascular inflammation that may reflect plaque vulnerability. Therefore, we analyzed which body size phenotypes cause the increased vascular inflammation using FDG positron emission tomography. We compared (18)F-FDG uptake, measured using the blood-normalized standardized uptake value, known as the target-to-background ratio (TBR), along with various cardiometabolic risk parameters in 250 participants without a history of cardiovascular disease. Body size phenotypes were classified according to body mass index and the presence/absence of metabolic syndrome. Cardiometabolic risk factors were significantly different among the body size phenotype groups. In particular, the maximum TBR (maxTBR) values in the metabolically abnormal but normal-weight, metabolically healthy obese (MHO), and metabolically abnormal obese groups were significantly greater than those of the metabolically healthy normal-weight (MHNW) group. Components of metabolic syndrome, insulin resistance, high-sensitivity C-reactive protein, and Framingham Risk Score were associated with maxTBR value. Interestingly, although the Framingham Risk Score of the MHO group was almost similar to that of the MHNW group, maxTBR value of MHO subjects was significantly higher than that of MHNW subjects (1.38 [1.20, 1.50] vs 1.22 [1.12, 1.37], p = 0.006). In conclusion, the present study suggests that unique subsets of body size phenotype, such as MHO or metabolically abnormal but normal weight, may have distinct effects on vascular inflammation.

Association between body size phenotype and sleep duration: Korean National Health and Nutrition Examination Survey V (KNHANES V).

OBJECTIVE: Recent studies reported the presence of unique subsets of body size phenotypes that are more susceptible or more resistant to the development of obesity-associated metabolic disorders, although the underlying mechanism is not yet fully elucidated. We investigated the association between body size phenotypes and sleep duration after adjusting potential confounding factors. MATERIALS AND METHODS: We analyzed data from the Korean National Health and Nutrition Examination Survey V (KNHANES V), a nation-wide, population-based health survey including 9077 Korean adults. The average amount of sleep per night was categorized as: ≤6, 7, 8, and ≥9 h. Body size phenotypes were classified based on body mass index (BMI) and presence of metabolic syndrome; metabolically healthy and normal weight (MHNW), metabolically abnormal but normal weight (MANW), metabolically healthy but obese (MHO), and metabolically abnormal obese (MAO). RESULTS: According to sleep duration, there were significant differences in age, gender, BMI, waist circumference, and blood pressure (all P <0.05). Multivariate analysis showed that obese groups (MHO and MAO) had significantly shorter sleep durations than non-obese groups (MHNW and MANW) (6.78±0.04 vs. 6.93±0.03, P <0.001). Sleep duration was significantly different according to body size phenotype, irrespective of confounding factors, such as age, gender, smoking status, alcohol consumption, physical activity, income, and education (MHO; 6.73±0.05, MAO; 6.82±0.05, MHNW; 6.94±0.04, and MANW; 6.91±0.05; P <0.001). CONCLUSION: Sleep duration is independently associated with body size phenotype after adjusting for confounding factors in the Korean population.

A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered hepatokine that mediates obesity-related metabolic disturbances. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel therapeutic agents for inflammatory disorders including nonalcoholic fatty liver disease (NAFLD). However, no research has examined the connections or functions of LECT2 and the novel DPP-4 inhibitor, gemigliptin, in NAFLD pathogenesis. High-fat diet (HFD)-fed C57BL/6 mice were used to investigate the effect of gemigliptin on hepatic steatosis and LECT2 expression. In the HepG2 cell line, LECT2 and gemigliptin signaling were analyzed by Western blot. LECT2 increased mammalian target of rapamycin (mTOR) phosphorylation, sterol regulatory element-binding protein (SREBP)-1 cleavage, lipid accumulation, and insulin resistance in HepG2 cells; these events were significantly decreased by treatment with a c-Jun N-terminal kinase (JNK) inhibitor. Gemigliptin increased AMP-activated protein kinase (AMPK) phosphorylation and inhibited tumor necrosis factor (TNF) α-induced mTOR phosphorylation, SREBP-1 cleavage, lipid accumulation, and LECT2 expression in HepG2 cells; these events were attenuated by an AMPK inhibitor. Gemigliptin recovered TNFα-induced inhibition of insulin receptor substrate (IRS)-1 and Akt phosphorylation that was abolished in LECT2 knockdown cells or by AMPK inhibition. In preliminary in vivo experiments, gemigliptin induced AMPK phosphorylation and inhibited LECT2 expression in liver tissues from HFD-fed mice. Mice fed with HFD and gemigliptin showed improved hepatic steatosis and insulin resistance compared to HFD-fed mice. Gemigliptin might alleviate hepatic steatosis and insulin resistance by inhibiting LECT2 expression by AMPK-dependent and JNK-dependent mechanisms, suggesting a direct protective effect against NAFLD progression.

The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms.

Recently, dipeptidyl peptidase-IV (DPP-IV) inhibitor, a major anti-hyperglycemic agent, has received substantial attention as a possible therapeutic target for inflammatory diseases such as atherosclerosis. However, the direct molecular mechanisms through which DPP-IV inhibitor mediates anti-inflammatory effects in vascular endothelial cells have not been clarified. The effects of the DPP-IV inhibitor, gemigliptin, were analyzed in human umbilical vein endothelial cells (HUVECs) and THP-1 cells. Using Western blotting, we demonstrated that gemigliptin efficiently increased the level of AMP-activated protein kinase (AMPK) and Akt phosphorylation in a dose-dependent manner. The levels of lipopolysaccharide (LPS)-mediated phosphorylated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) were significantly decreased after gemigliptin treatment. Furthermore, gemigliptin reduced LPS-induced expression of adhesion molecules and inflammatory cytokines such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1ß (IL-1ß), and IL-6 in HUVECs. In macrophage-like THP-1 cells, gemigliptin effectively inhibited LPS- and low-density lipoprotein (LDL)-induced foam cell formation. However, these anti-inflammatory and anti-atherosclerotic effects of gemigliptin in HUVECs and THP-1 cells were significantly reduced after treatment with an AMPK or an Akt inhibitor. Our results suggest that gemigliptin efficiently inhibited LPS-induced pro-inflammatory effects in vascular endothelial cells by attenuating NF-κB and JNK signaling via Akt/AMPK-dependent mechanisms. Therefore, the DPP-IV inhibitor, gemigliptin, may directly protect the vascular endothelium against inflammatory diseases such as atherosclerosis.

Implications of Pericardial, Visceral and Subcutaneous Adipose Tissue on Vascular Inflammation Measured Using 18FDG-PET/CT.

OBJECTIVE: Pericardial adipose tissue (PAT) is associated with adverse cardiometabolic risk factors and cardiovascular disease (CVD). However, the relative implications of PAT, abdominal visceral and subcutaneous adipose tissue on vascular inflammation have not been explored. METHOD AND RESULTS: We compared the association of PAT, abdominal visceral fat area (VFA), and subcutaneous fat area (SFA) with vascular inflammation, represented as the target-to-background ratio (TBR), the blood-normalized standardized uptake value measured using 18F-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) in 93 men and women without diabetes or CVD. Age- and sex-adjusted correlation analysis showed that PAT, VFA, and SFA were positively associated with most cardiometabolic risk factors, including systolic blood pressure, LDL-cholesterol, triglycerides, glucose, insulin resistance and high sensitive C-reactive proteins (hsCRP), whereas they were negatively associated with HDL-cholesterol. In particular, the maximum TBR (maxTBR) values were positively correlated with PAT and VFA (r = 0.48 and r = 0.45, respectively; both P <0.001), whereas SFA showed a relatively weak positive relationship with maxTBR level (r = 0.31, P = 0.003). CONCLUSION: This study demonstrated that both PAT and VFA are significantly and similarly associated with vascular inflammation and various cardiometabolic risk profiles.

Adipose gene expression profiles related to metabolic syndrome using microarray analyses in two different models.

BACKGROUND: Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist has a wide-ranging influence on multiple components of metabolic syndrome. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a useful animal model of metabolic syndrome. To determine genes related to metabolic syndrome, we examined overlapping genes that are simultaneously decreased by PPAR-γ agonists and increased in OLETF rats using microarrays in two different models. METHODS: In the first microarray analysis, PPAR-γ agonist-treated db/db mice were compared to standard diet-fed db/db mice. In the second microarray analysis, OLETF rats were compared to Long-Evans Tokushima Otsuka (LETO) rats (control of OLETF rats). RESULTS: Among the overlapping genes, in the present study, we validated that lipocalin-2 expression was significantly decreased in the visceral adipose tissue of PPAR-γ agonist-treated db/db mice compared to standard diet-fed db/db mice and increased in OLETF rats compared to LETO rats using real time reverse transcription polymerase chain reaction. Furthermore, we showed for the first time that lipocalin-2 expression was significantly increased in the visceral adipose tissues of obese humans compared with nonobese humans. In addition, the expression level of lipocalin-2 in human visceral adipose tissue had a significant positive correlation with body mass index, serum interleukin-6, adipocyte fatty acid binding protein levels, and white blood cell count. CONCLUSION: Lipocalin-2 was confirmed to be a significant adipokine affected by PPAR-γ agonist and obesity in the present study. Also, for the first time in human visceral adipose tissue, it was determined that the expression of lipocalin-2 from obese humans was significantly increased and correlated with circulating inflammatory markers.